Semicarbazones of desa-pregn-9-ene-5-ones

ABSTRACT

THIS INVENTION IS DIRECTED TO SUBSTITUTED DESA-PREGNENES AND DERIVATIVES THEREOF WHICH ARE CONVERTED TO SEMICARBAZONES THEREOF AND SUBSEQUENTLY CONVERTED TO KNOWN 9B, 10A-STEROIDS OF THE PREGNANE SERIES. THE LATTER COMPOUNDS ARE USEFUL AS BOTH PROGESTATIONAL AGENTS AND AS SALT-RETAINING AGENTS.

United States SEMICARBAZONES F DESA-PREGN- 9-ENE-5-0NES Milan Radoje Uskokovic, Upper Montclair, NJ assignor to Holfmann-La Roche Inc.,.Nutley, NJ.

No Drawing. Application June 13, 1968, Ser. No. 736,587,

which is a division'of application Ser. No. 499,094,

Oct. 20, 1965, which in turn is a continuation-in-part of application Ser. No. 400,206,- Sept. 29, 1964,now Patent No. 3,412,107. Divided and this application May 24, 1971, Ser. No. 146,422

Int. Cl, C07c 133/02 U.S. Cl. 260-554 1 Claim ABSTRACT OF 'THE DISCLOSURE This invention is directed to substituted desA pregnenes and derivatives thereof which are' converted to semicarbazones thereof and subsequently converted to known 9,8,l0oc-St6l0ldS of the pregnane series. The latter compounds are useful as both progestational agents and as salt-retaining agents. a

" 'RELATED APPLICATIONS This application is a division of applicants copending application Ser. No. 736,587, filed June 13, 1968, which is a division of applicants copending applicationSer. No. 499,094, filed Oct. 20, 1965, entitled, Intermediates and Processes, which is a continuation-in-part of applicants copending application Ser. No. 400,206, filed Sept. 29, 1964, entitled Intermediates and Processes, now US. Pat. No. 3,412,107, issued Nov. 19, 1968.

DETAILED DESCRIPTION OF THE INVENTlO'N Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long'periods of time and, in comparison with purely chemical-reactions,"

are very inefficient and give only small yields.

It is an object of the present invention to provide intermediates and processes which enable the preparation of 95,10a-steroids without the necessity of proceeding through a photochemical reaction. It is also an object'of this invention to provide novel intermediates'and processes which will enable the further exploration of steroids having the unnatural 9fl,l0a-configuration. It is also an object of this invention to provide novel 96,10m-steroids.

The novelintermediates and processes of this invention are valuable and provide a new synthetic route com pletely of a classical chemical nature, ie involving'no photochemical reaction, for converting steroids having the normal configuration into steroidal'compounds possessing the unnatural 9p,10a-configuration.

3,766,268 gate nted oct 1 6,.

In one aspect, the novel intermediates and processes of this invention enable the preparation of 9B,]Ou-steroids of the androstaneseriese of the formula wherein R is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen "or lower alkyl and R and R taken together, are selected from the group consisting of (l7[3OH, l7a-lower alkanoic acid lactone) and 0x0; R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the 6- or 7- position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen.

Compounds of Formula I are useful as anabolic agents.

Other 9fi,10a-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae ---lower alkenyl /wv R| III wherein R ,R Y and X have the same meaning as above. Compounds of Formula 111 are useful as progestational 'agents'and compounds of Formula II are useful as'anti-androgenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention enable the" preparation of' 9B,10a-ster0ids of the 17,6- pregnane series'of the formulaclan-Rt wherein R R Y and X have the same meaning as above.

Compounds of Formula V are useful as salt-retaining agents, i.e. are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both well as substitutes therefor such as l tertiary amino-3- butanone,- :1-tertiary amino-3 pentanone "and q ate y ammonium salts thereof), I-Qbutan-B-Qne, 1-Q-butau-3- one, lower alkylene ketal, l-Q-butan-El-ol, esterified l-Q- butan-B-ol, l-Q-butan-S-ol ether, 1,3dichlorobut-2-ene, 1,3-dichloropent-2-ene, 1-pentan-3-one,' 1*,Q-pentan-3-pne lower alkylene ketal, l-Q-pentan-Z-ol, esterifiedql-Q- pentan-B-ol or I-Q-pentan-3-ol ether, whichjcondensation yields the desired 9 8,10a-steroids. The symbol Q is bromine, chlorine or iodine, with theformer two being preferred. This invention also provides a number of different methods for the preparation'of' said -desA-androst-9een-5- one or desA-'175-pregn-9-en-5-one starting materials. from natural steroids. 7

In one embodiment, a steroid of the '3-orro-androst-4- ene or 3-oxo-rl7p-pregne4-ene series is subjectedtoan oxidative ring epening of 'the; A-ring yielding -a 5-oxo- 3,5-seco-A-norandrostan-3oic acid or; a '5i-o o 3',5 -seco- A-nor-flflefpregn an-3 oic aci which Sa i acid can then be converted toamixtiire of a l'0iwdesA-androstan 5-one and, a 1.1QB-desAhhdfStan-S-one or a mixture of a 1011' desAel'lfi pregnand-one and a ltl s desA- l'lfl-pregnandone. The conversion of the 3-oic aicidtoithe. desA-compound can be effected either by pyrolysis of 'a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oxo-androste5- en-3-one or a 4-oxo-l'lfi-pregn-S-en-B-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted. into the desired ,desA-comstraight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl andthe like. Similarly, the termlower 'alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups, e.g'. formyloxy acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehendsall four halogen i.e. iodine, bromine, chlorine and fluorine.

The expression (1713-OH, 17a-lower alkanoic acid la'ctone) refers to a configuration; ontheC-17 carbon,

atom illustrated as follows: 7

- Q 7 it 7 17 wherein W is lower alkylene, e.g.'polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position. t

In one aspect, this invention comprises a method "for the preparation of 9B,10a,-androstanes of Formulae -I.III

and of 9fi,l0a-l 7fi-pre'gnaries ,of Formulae IV-VWhich comprises the hydrogenation of. 'desA-androst-9 ene5-ones or of desA-l7;3-pregn-9-en-5-ones re 9/3,l0;3-desA-androstan-S-ones or 95,lOB-desA l7fi-pregnan-5-ones, respectively, followedwby condensation with a lower alkylgvi nyl ketone with f methyl or ethyl vinyl ketone preferred (as pound. The des'A-cornpound can then be converted into the starting material desA-androst-9-en-5-one or desA- 17B-pregn-9-en-5-one via a two-step sequence of halogenation' and dehydrohalogenation.

"In another'embodiment of this invention, desA-andro'st- 9-en-5-one or desA-l7B-pregn-9-en-5-one starting materials can be prepared from} l-hydroxy steroids of the 3-oxo-androst-4-ene or 3-oxo-l 7fi-pregn-4rene series. This can be effected in a' variety'of Ways. 'In one approach, an ll-hydroxy group of; asteroid of the 3 oxo androst-4- ene or 3-oxo-17B pregnA-ene series is converted into aleaving group, for example, a sulfonic'acid ester or carboxylic acid ester. Qxidative ringopening of the A-ring of the thus formed ll-(esterified hydroxy -containing compound yields the. corresponding ll-(iesterifiedhydro3y)-5 oxo'- 3,5 seco A-norandrostan-3-oic acid or ll-(esterified hydroxy) 5 oxo fifi seco-A-nor 17B- pregnan-3-oic acid which upon pyrolysis. of a salt of said B-Oicacid yields the desired desAandrost-9-en5-one or desA-l7fl pregn-9-en-5-one starting material, l V 'A further approach involves formation. of an ll-hydr'oxy-dsA-androstan-S-one or 11 hydroxy-desA-17,6-v

pregnan-S-One from an ll-hydroxy steroid of the 3-oxoandrost-4 ene or 3-oxo-l7fi-pregne4-ene.series via an oxi dativering opening of the' 'Auing .of said ll-hydroxy steroid which yields-an ll hydroxy-5-oXo-4-nor-3,5-secoandrostan .-.3 -oicacid 3,1l-lactone or an ll-hydroxy-S- (pro- 3,S seco I7l3 pregnan-3-oic' acid 3,1l-lactone which, in turn is converted into a salt of the corresponding .keto acid which salt upon pyrolysis gives the 1- l-hydroxy-desAw androstan-S-one or 11 hydroxydesAl-7fi-pregnan-5eone.

Esterificationof the Il-hYdI'OXYiIIlOlCtY of the so-obtained compound with an acid moiety yieldsan 11-(esterifiedv droxy) -desA-l7/3-pregnan-5 one which upon elimination of. the leaving group (i.e., the esterified hydroxymoi'ety) gives the desired ,desA-androst-9-en-5rone or desA-l7 8- pregn-9-en-5-one starting material. T hough, in the above reaction sequence'either*11a-OI-f or 11fiiOl- I starting material steroids can be used, it ispreferredto use 1-la-- OH starting materials. 1

' As will pe appreciated from the above discussiomineitherthe specific reaction, steps nor the reaction sequences ofthisinvention involve any modification of substituents found in the 16- and/or 17-position. of the; starting material natural steroids. However, in order to obtain unnat uralQflJOa-s'temids of Formulae IV,. it isnecessary or desirableto protect certain of the 16- and/or 17-substituents. against'one or more of the'reaction steps involved. It is also convenient to initiallyprotectsuch a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of Formulae I-V possessing the unnatural 95,10a-eonfiguratin is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are exemplified by the 16- hydroxy group in a compound of any of Formulas I-V, the 17/3-hydroxy group in a compound of any of Formulas I-III, the l7a-hydroxy or -oxo group in a compound of any of Formulas IV-V, the 21-hydroxy group of a compound of Formula V or thel7-oxo group of a compound of Formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, to yield a 17-lower alkylene .dioxy or 20-lower alkylene dioxy compound, i.e., a 17-k etal or a ZO-ketal.

The 1fi-hydroxy,17a-hydroxy,17;3-hydroxy or'21-hydroxy moieties-can be protected by esterification and/or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently be bydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, eg acetic acid, caproic acid, benzoicacid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the 16a-hydroxy, 1-70;- hydroxy, or 21-hydroxy substituent can be effected by forming the lower alkyl ortho ester thereof, i.e. 1604,1711- or 17a,21-lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benz-hydryl and trityl ethers, or a-lower alkoxylower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

In compounds containing the dihydroxyacetone side chain at C-l7 (for example, compounds of Formula V wherein R is hydroxy), the side chain at C-17 can be protected by forming the 17,20; 20,2l-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,21-diester. The 17,21-acetal or ketal and l7,21-diester hinder the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,20; 20,2l-bis-rnethylenedioxy derivatives actually convert the ketone to a non-reactive derivative. When both a l6a-hydroxy and l7a-hydroxy substituent are present, these groups can be protected via formation of a 16a,l7a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 17cchydroxy nor 2l-hydroxy substituent but there is present a 20-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the l7-acetyl side chain can be protected via conversion to a 17-(a-hydroxyethyl)-side chain. Regeneration of the l7-acetyl side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid Similarly in compounds containing a 17-oxo, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the 17-oxo group can be reduced to a 17flOH, 17a-H moiety, from which, when desired, the 17-oxo moiety can be regenerated'by. oxidation, as described above. Furthermore, a20-hydroxy .or 17B-hydroxy group, can itself be protected by esterification, for example, with a lower, alkanoic acid such as acetic acid, caproic' acid, or the like; or byetherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The 16091701, or 17a,2lacetals and ketals above discussed can be formed by reacting l6u,l7u-bis-hydroxy or'17a,21-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected. 7

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl, o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alk'yl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as 1, -l,1-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fiuorobenzaldehyde), lower alkoxy-bendal-deh'ydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyD-benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, fl-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substitute'd halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, oz,or,octrifluoroacetophenone, propiophenone, but'yrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p chloroacetophenone and p chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,pxylyl methyl ketone; benzophenone, and monoor hissubstituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and 1-phenyl-4-pentanone, and aromatically substituted derivatives thereof. I

Especially suitable are those aldehydes or ketones which, with the :,l7aor l7u,-21-bis-hydroxy grouping form an acetal or ketal group of the formula wherein P is individually selected from the group consisting of hydrogen and lower alkyl; Q is individually;

-m'ention of any substituent' comprehends th'evarious' pro v 'androstan-S -onesor 918,lfifiedesAmregnanefi-ones oi he i F fi I? i prepared frorn9,8,1()fl-desA-androstand-ones of Formiila I 'VIII and 9-B,lOwandrostanes of Formula III from 93,1013- racmflt selected from the group consisting'of lower alkyland Moreover, 9/3,l0a-175-pregnanesof Forrnnlae lv and" 'aryl; and P and Q taken together arelower alkylenen I -V can be prepared from 9B, 10fi-desA-pregnan-5-ones of The ter i,l0'wer alkylene comprehends p lymethyiene' Fpmmlae X and X'Lmspwtwely I '7' chains such as tetramethylenea'n'd pentam'e'thylene." V cHlP-Bl tIn'discussing the various starting materials, intermediatest and end-products. of this'invent ion, the'various 1 protecting groups discussed'above will not necessarily be' specifically mentioned,sbut it should be understood that tectedforms thereof, unless specifically mentioned to the contrary.' V I a it In one; embodiment ofthis invention; compounds of:

Formulas'l through V areprepared from "915,IOB-desA5 wherein X has the same meaning as above and D reprewherem R6, and X have the samelmeamng as sents the carbon and hydrogen atoms necessary to com above' a a V a I pletethe steroid Daring, aswell as the: atoms in the The conversion of a 9B,10,8-desA-'compo1mdof Forsubstitnents in the 16- and 17-positions, as defined in 1 mulaVItoa'9fl,10asteroid of Formulael-V (iie-g VII- 1, Formulae I-V above. 1

Thus, 98,10a-androstanes ofFormula Ican-beprepared; densmg the 93 510B 'dgsA'icpmp'ound; with} comPQuBdhse from 5 i idesA'arndrorstan's'ones of the formula tone (as Well as substitutes therefor such as l-tertiary amino-3-butanone; l-tertiary ammo-3-pentanone andqua-t ternary ammonium salts thereof), l,3-dichlorobut2r-ene,

a y 7 y 1 vinyl ke one and 5Hertiaxy amino y, an 4 'ferred reagents and the former is especially preferred. I Prior to the condensation it is desirable to proteet the-20- e e '5 keto group present inicomponnds of FormuiaeX andxr, Wherem R2 R3 and X have the Same'metanmg as then it is not necessary to protect :,170: or 21i-hydroxy '7 lected from the group consisting of lowerjalkyl vinyl ke I or iodo, with the formertwo being preterred: Methyl :hut ano n rare thepre Similarly, ;9;3,1Qa-androstanes ;,Qf Formula' II ,can be groups which. are present, rbnt;groups protectinggthese.r

a The above, indicated snbstitnteslfbr Iowa aikyi vinyl 'ketones are compounds'wherein the vinyl moiety isrerplaced by a moiety of theformnla' 1 .t r. r r e desA-androstan-S-ones of FormularlX. t 7 e V a n a T wherein'each Rislovver alkyl or taken togetherlboth'R s ene. Such moieties are, for example, dimethylamino,di1-

via the utilization of conventional qnaternizing'agents, for

V henzyllhalides, mesylates or tosylates;

'tion partner for the condensatiomring closure to ringA of'Formnlae I V occurs simultaneously wi sationr Howevenwhen 13-dichibrobutw t ropent-l-ene, l-Q-butan-li-one lower alkylen ketal l-Q- r y a 7 5; pblgltaib3-0l5 l- Q-bntan-i ol etheryesferi'fidi wherein R Ryand X havieithe same meaning asflabove; vol, l Q pentan-r3 one lower alkylene lcetal 0 moieties can be retained throughfthe; condensatienre w so I are; lower alkylene;oxadower alkylene or aza -lew er alkyl aethylamino, pyrrolidi no piperidino; morphol-ino, or the" A A like. The quaternary ammonium salts thereofare formed example, lower 'alkyl'ionphenyldower alkyl} (especially I When a lower alkyl vinyl ketone or' suh stitute' therefor, I-Q-butan-one or l Q-pentan-i3rone is usedl as the reacia 7 0; (containing a'3-oxo moiety) of the desiredgame-steroid j a J hthe eondejn -g --j e,- 13 -dich 1o- 7 the 3-oxo moiety is required... When-:l-Q-butandol; or 1-;

Q-pentan-3-o1 is used as the reaction partner,the .oxo moiety can be generated-by.oxidationrandforzthis put--v pose, it is suitable for use oxidationmeans known per-se,-

for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified l-Q-buta'n-3- 01 or esterified or etherified l-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkauoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting such. 1-Q but'an-3-ol or l-Q-pentan- 3-01 esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkalimetalhydroxide such as aqueous sodium hydroxide. Suitable ethers are, for example, lower alkyl ethers, i.e. 3-methoxy, 3-ethoxyor the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an'aqu eous mineral. acid suchas-hydrochloric acid, sulfuric acid or the like. Whena l Q- butan-3-one lower alkylene ketal or a I- Q- entan-B-one lower alkylene ketal is used as the reaction partnen, mild acid hydrolysis of the ketal moiety results in genei'ation of the 3-oxo moiety. Finally, when 1,3-dichloro but-3-ene or 1,3-dichloropent-3-ene is used as the reaction partner, the 3-oxo moiety can be generated'by treatment with a concentrated mineral acid, preferablya strong acid such as hydrochloric acid'or sulfuric acid; Itshould be noted;

that 1,3-dichlorobut-2-ene and 1,3-dichloropent 2-e ne' may be used as reaction partners with compounds of Formulae X and XI, but not with the 17a-lower alkyl, alkenyl or alkynyl compounds of Formulae VIII-IX. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of Formulae IV wherein Y ishydrogen is obtained. Similarly, when a reaction partnerbased on pentane is utilized a compound of Formulae IV wherein Y is methyl is obtained.

In addition to the preparation ofcompounds. of Formulae IV from compounds of Formulae VI- XI by the use of the above mentioned reaction partners, ,it is' also possible by the procedures of this invention to. prepare compounds of Formulae IV which, in the A-ring, in addition to containing an unsaturation betweenthe fland S-positions also contain an unsaturation between .the l-i and 2-positions. Such 1,4diene' productscorrespondin'g to' the compounds of Formulae IV can be prepared from compounds of Formulae VI-XIby condensation of the latter with a reaction partner selected 'from the group consisting of ethinyl methyl ketone'and ethinyl ethyl ke' tone (as well'as substitutes therefor such as fi-t'ertiary v amino-vinyl methyl or ethyl kctone, quaternary ammo nium salts thereof, and fi-loweralkoxy-vinyl methyl or ethyl ketone). Condensation to prepare sucha 1,4-dierie product corresponding to the compounds of Formulae' IV is effected under the same conditions as is the condensation to prepare a compound of Formulae ,I-V. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-ene-compounds mulae IV. 1 l

The condensation is suitably eifected at, below or above room temperature. For example, at the refluxt'emperature of the reaction medium or at ice temperature (C.) or below. Moreover, the condensationis suitably effected in an organic medium. Preferablythe solvent a loweralf kanol, such as methanol, isopropanol, 'tert-butanoL eth-L anol, or another non-ketonic organic solvent, such aslan. ether, e.g. dioxane, diethyl ether, dii sopropyl' etheglar'd' matic hydrocarbon, e.g. benzene, toluene, xylene, organic acid, such as acetic acid, or thelike. Lower alkanols are the preferred solvents. It is suitable to catalyze the on-g densation, and this can be effected via us e ofa catalyst such as an alkali metal lower alkoxide, for example so;

pared via hydrogenation of DesA-audrost-9-en-5-ones of the formulae Hac R1 --lower alkenyi X XIII ---lower alkynyl XIV ' 3- butanone, l-tertiary amino-3-pentanone and B-tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups: are dilower alkylamino' groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed 'from' lower alkyl halides such as" mehyl iodide." An exemplary fi-lowr alkoxy vinyl methyl or ethyl ketone is 'fi-methoxyvinylethyl'ketone.

-'One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones v or" desA-pregn-9-en-5-ones to 98,10,B desA-androstau 5-ones of Formulae VII-IX or to 9B,IOfl-desA-pregnan-S-ones of Formulae XXI. Thus,

9/3,1OB-desA-androstan-S-ones of Formula VII can be preexi-S-ones'of the formulae Cilia-Rs V 11' a a p Q mong I 2:0: mgi j V' V :7 HzC i wherein R'g, :R R5 and "have. the same meaning. as i 1 above s. V ..,Prior.'to hydrogenatiom the C- 2 0 keto group in pounds of Formulae XV and XVI or C-.1 7 keto groupiin compounds oii Forninla XII should beprotected either conversion'to the corresponding. carbinol or by .ketaliza- 2o the "7 tionas described above. The-hydrogenation can, however, be effected without protectingsueh keto groups.

- Moreover, it should be notedthat the hydrogenation,

besides inserting a hydrogen atom in each of the 9-. and

10-positions, can also simultaneously teifecthydrogenaw tion of other groups in the molecule. For example, the- 5 0-20 keto group can be hydrogenated to the corresponding carbinolror the C-17 lower alkenyl group'in com-1 pounds of Formula XIII or the 0-17 lower alkynyl group in compounds-of FormulaXIV can be hydrogenated to the corresponding (3-17 lower alkyl compounds. Cornpounds, of Formulae VIII and IX can, in' turn, be prepared from compounds of Formula VII wherein R and R together are 0x0 via reaction with a loweralkenyl or lower alkynyl Grignard reagent, with prior protection of theS- keto group, for example, by forming S-ketals without concurrent blocking of the 17-keto group. In the same manner compounds of Formulae XIII--and XIV can be formed from compounds of Formula XII wherein R and R taken 7 together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of Formulae XII-XIV and of desA+pregn-9-en'-5-o'neso1 I Formulae XV-XVI is oneof the" main features of this invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, rutheniumfand rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example,

rhodium oncharcoal (or carbon powder, carbon black,

or the like) or rhodium onalumina. In contrast to what would be expected, it has been found that'such a catalytic hydrogenation of a compound of Formulae XII-XVI gives a substantial yield of a compound of Formulae VI-XI. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the Formulae V'I-XI. This catalytic hydrogenationis suitably effected in an inert organic solvent, forexample,

a lower alkanol such as'tmethanol'or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cy-. clohexane, hexane, or the like. Lower alkanols are .pre

ferred solvents. Moreover, it'is suitably conducted in the presence of an acidic or basic catalyst, "for example, an alkali metal or: alkaline earth metalthydroxide such as sodium hydroxide or the like, or a mineral acid, for

example, a hydrohalic acid, such as. hydrochloric acid,

or the like, or an organic acid such as a lowerfalkanoic 7 acid, for example, acetic acid. The reaction can be conducted at, above or below room temperature;'for example, from about -5 Cato about 100 C. However, it, is preferably conducted at'a temperature between about 0 C. and about 35C;

As described above, the desA-androst-9-en-5mnes or desA-17,8-pregn-9-en-5-ones ,of Formulae XII-XVI can be prepared from natural steroids by a variety of methods. Thus, in one embodiment of this invention said desA-androst-Q-en-S-ones or desA-17,8-pregn-9-en-5-ones can be prepared from steroids of the 3-oxo-androst-4-ene I or B-oXO IW-pregn-A-ene series by a reaction sequence which involves as a firs't-stepan oxid'ative ring opening V of ring-A of the naturalasteroid. For this oxidative ring opening there can -be used as starting materials, natural 7 steroids 'of the'3-oxo-androst4-ene or 3-oxo-l7p-pregn- 4aeneseries 'of thetormulaz Y Q 'x' XVII orisis'ting. of hydrogen, lower alkyl,

, )lower 'alkyl, lower alkylthio, lower alkanoyli logen, andZ represents the carbon andihy- "I rog'e'n' a msnbcessary to'complete the steroid D- ellas -thefatoms' in the 'sub'stituents in the o'sitionsas defined in Formulae I, IV,-and

Ihe bxid ative" of alnatural' steroid ofi I Formulatxyllyieldsg a:i oxogfiseeo Agnorandrostam3 Oic-acidor a 5-oxo-3,5-seco-A-norpregnan 3-oic' acid of 'theformula wherein X" and 2 have the same meaning as above.

i. ,Ihe .loxida'tiv ring: opening i of the compound of FormiflaXVIIIca 'In "alpreferred' embodiment it is etfectedflby ozonolysis. The'o'zonolysisfissuitably,carried out in an organic solveng for.exarnplefacetie acid, ethyl acetate, methanol,

chloroform, methylene chloride, or the like, or a mixture of. two or more of such solvents such asethyl acetate/ acetic acid, ethyl acetate/ methylene; chloride, or the like. Moreover, the, ozoiiolysis isladvantageously. conducted at new room temperature. Thus, it is preferably conducted at ajternperaturfe betweenfabout C. and about 25 C. The resulting ozonides can be decomposedby conventional ineana tor example, by treatment with Water,

' hydrogenperoxide in water, acetieaoid or ethylacetate,

or'the likei lh e oxidative ring opening of a compound of F'or mula XVII toa compound'of Formula XVIII can also be'efiectedbyother oxidation means, for example, by. treatment witlr'hydrog'en peroxide. It should be'noted that an oxidative ring opening by either ozonolysis or by treatment withhydrogen'"peroxide, does not require rotection of any; of the substituents at 0-16 or C-17. Mowever, asstated above, it maybe desirableto protect these 7 V substit ients against some; subsequent reaction in the total reaction-sequence being practiced On the other: hand, the

oxidative ring opening can also be effected by oxidation" with chromiuni trioxide or via treatment with sodiumi period'atefand potassium permanganate in potassium carp bonatefsolution and ifthese oxidation means are'used, 70

is necessaryto-protect any secondary hydroxy groups ight be present'such as a '16.,1'75- or 2l-hydroxy non-aromatic protecting groups.

I l oll'owing the oxidative ring opening of the A-ring, the so-obtained 5-oxo-3,5-seco A-norandrostan-B-oic acid or stitutent in [the o pos ition" selected" h floweral-kanoylthio o'r a substitueritl =po'si'tion' selected from the group consisting of iiibe performed by a yariety of methods.)

preferably, for the purposeof this reaction with -oxo-3,5-seco-A-norpregnan-3-oic acid of Formula XVIII is converted into a mixture of a IOa-desAQandrQStan-S-One and a IOfl-desA-androstan-S-one or a mixture of a desA-pregnan-S-one and a lOfl-desA-pregnan-S-one as illustrated below:

XVIII alkali metal salt of XVIII wherein in Formulae XIX and XX,

X and Z have the same meaning as above.

The compounds of Formula XIX are lOa-desA-andmstan-S-ones or 10a-desA-pregnan-5-ones, depending on the meaning of Z, and the compounds of Formula XX are lOfl-desA-androstan-S-ones or 1OB-desA-pregnan-S-ones. The conversion of a compound of Formula XVIIIinto the compounds of Formula XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of Formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxideor in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture .of sodium acetateand potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200 C. to about 350 C. in the presence of aproton acceptor, eg, an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e. at a pH greater than 7 The pyrolysis can be effected in solution or by fusion. An. especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of Formula XVIII in a basicorganic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine. isoquinoline, quinoline, triethanolamine, or the like. When utilizng this approach using a basic organic solvent it is suitable to heat to temperature between about 200 C. and about 300 C., and preferably between about 230 C. and about 260 C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of Formula XVIII to compounds of XIXA wherein X and Z have the same meaning as above.

The compounds of Formula XIX can be prepared from compounds of Formula XIXA in the same manner that compounds of Formula XIX are prepared from compounds of Formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of Formula XIXA followed by elimination of the residue of the A-ring, to yield a compound of Formula XIX. The oxidative ring opening of the compound of XIXA can be performed byozonolysis as described above for the conversion of a compound of Formula XVII to a compound of Formula XVIII. Such ozonolysis of a compound of Formula XIXA yields a compound of the formula XIXB wherein X and Z have the same meaning as above, and A is carboxy or formyl.

A compound of Formula XIX'B can then be converted to a compound of Formula XIX. This removal of the residue of the A-ring, i.e. decarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of Formula XIX, but also a minor yield of the corresponding lOfi-isomer of Formula XX.

Comopunds of Formula XIX can also be formed from a compound of Formula XVIII via the formation of an enol-lactone of a compound of Formula XVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxopregn-5-en-3-one of the formula:

XXI

wherein X' and Z have the same meaning as above 0115 XXII wherein X and Z have the samemeaning as above,

which, upon treatment with an alkali metal hydroxide,

' such as potassium hydroxide, at an elevated temperature;

for example, from about 200 'C. to about 240' C., is

converted to the corresponding l0a-desA-androstan-5-one or 10a-desA-pregnan-5-one of Formula XIX.

It should be noted that though the pyrolysis of a compound of Formula XVIII yields both the lOfi-compounds of Formula XX and the wot-compounds of Formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydro-halogenation steps of' this reaction sequence, it is sometimes preferable to convert the 10fi-compound of Formula XX into the corresponding mix-compound of Formula XIX. This conversion can be effected by treating a 10/3-desA-androstan-5- one or 10/3-desA-pregnan-S-one of Formula XX with any base capable of producing a carbanion; for example, it is 7 suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodiof an alkali metal carbonate (e.g. lithium carbonate) or um ethoxide in an ethanol solution or sodium methoxide in a'methanol solution. 7

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of Formula XVIII 'tocom' pounds 'of Formulas XIX and XX can be eifected without protection of any of the substituents which might be present. at C-16 or C-17. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of Formula XVIII to compounds of Formulas XIX and XX can beeifected with protecting groups present on substituents in the C-16 or C-17 position,

As stated above, the 10a-desA-androstan-5-ones or 100:- desA-pregnan-S-ones of Formula XIX. or the 10,8-desA- androstan-S-ones of 10fl-desA-pregnan-5-ones of Formula XX can be converted via a two-step sequence of halogenation andtdehydrohalogenation into the desired starting material desA-androst-9-en-5-one or desA-pregn-9ren-5- one of Formulas XII, XV, and XVI.

' In a preferred embodiment a IOu-desA-androstan-S- one or a l0e-desA-pregnan-5-one of Formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation. Halogenation of a compound of Formula XIX or a compound of Formula XX yields a mixture of corresponding halogenated compounds including one of the formula wherein'X' and Z have the same meaning as above, 7 and Hal is a halogen atom(preferably Br or Cl).

. Dehydrohalogenati-on .of a.-,compound of Formula,

xXnI V mulas XII, XV and XVI. Keto groups except for theS- keto group, may require protection prior to the halogena I tion. In the caseof compounds of Formulas XIX and XX containing the C-17 dihydroxyacetone side chain,

represented in'Formula. V wherein R is hydroxy, this protection can be etfected by formation of the 17u,2Q; 20,2l-bis-methylenedioxy derivative. In other cases wherein' a C-'-17 0x0 or 0-20 0x0 group is present, protection can be eitected by reduction to the: corresponding carbinol either directly prior to the halogenationt step or prior to some other steptin the reaction sequence leading to the compounds of Formulas XIX and XX.

The halogenation can be effectedwitlr halogenating agents such as bromine, sulfuryl chloride, or the like.

Brominationis especially preferred. The bromination is suitably effected; treatment with bromine at room temperature or below, preferably at ice temperature or below.

Suitably it is conducted 'in an organic medium; for example, an organic acid such as acetic acid} an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide'as a catalyst. When eifecting halogenation with sulfuryl chloride, it is suitable to use the same type or organic medium as when brominating; and suitable catalysts are, for example, acetic acid, benzoyl peroxide, or the like.

The subsequent-dehydrohalogenationof a compound of FormulaXXIII is preferably conducted under mild dehydrohalogenating conditionsyfor example, by the use an alkali metal halogenide (e.g. La lithium halide) in an Organic solvent such as a'di-lower alkyl-formamide,or with an organic base such as collidi'ne, pyridine, or the like. The dchydrohalogenation' is advantageously corn ducted at slightly elevated temperatures, for example, from about 50 C. to about 150 0., preferably from about C. to about C. I

Separation of the desired product desA'-androst-9-en-'- 5-one or desA-pregn-9-en-5-one of Formulas XII, XV and XVI can be effected by conventional means; As indicated above the halogenation procedure'may result in halogenated by-products in addition to the desired intermediate of Formula XXI-II. Accordingly, the separation is preferably effected after 'first subjecting the reaction mixture to dehalog'enating' conditions in orderto deha-logenatetthe halogenated by-productsfformed by'the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalog'enation thereaction'mixturecan theneasily be separated by conventional means, for example, by column chromatography,to yield the desired compound of Formulas XII, XV',IXVI. An examplary dehalogenation'means is treatment, with zinc and sodium acetate in an acetic acidsolution at an elevated temperature, for example, about ,80" C.

In the case of compounds of Formulas XIX'or XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such a halogen atom against dehalogenation prior to' subjecting the compound of Formulas XIX or to the'two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to a keto group, is illustrated in a compound of Formulas IV or V wherein R or R 'is halogen. Thus, if 10aor 10fl-desA- As stated above, the desired desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones, starting materials can also be stituent. In one embodiment an llhydroxysteroid ofthe formula r wherein X and Z have the same meaning as above, is reacted with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive derivative is meant, for example, a halide, e.g. a chloride, an v anhydride, or the like. Though either lleor lla-hydroxy starting materials can beused, it is preferable to utilize a-hydroxy compounds of Formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in ,the C716, C-l7 or C 21 position. Suitable acids for the esterification of the ll-hydroxy group,1which can be used to form a leaving group in the ll-position are inorganic acids such as phosphoric acid, organic ,carboxylic acids such as anthraquinone fi-carboxylic acid or organic sulfonic acids, .for example, toluene-sulfonic acids, especially p-toluene gsulfonic acid, lower alkyl sulfonic acids such as methanesulfonic acid and nitrophenyl-sulfonic acids, especially pnitrophenylsulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of Formula XXIV with a sulfonyloxy forming moiety, then a compound of Formula XXIV having an Ila-configuration should be used as a starting material. The abovedescribed,esterification of ll-hydroxysteroid starting materials of Formula XXIV yields compounds of;the formula.

, LOW

LO represents the leaving group.

In the next step of this reaction sequence, the so-formed ll-(esterified hydroxy)-compound of Formula XXV is subjected to an oxidative ring opening of the A-rin-g to yield the corresponding ll-(esterified hydroxy)-5-oxo-3,5- seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy) 5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula wherein X and Z have the same meaning as above, and

-. v x xxvr wherein X, Z and LO have the same meaning as above.

The oxidative ring opening of the A-ring of a compound of Formula XXV to a compound of FormulaXXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. Pyrolysis of the so-fornied compound of Formula XXVI under the conditions described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulas XIX and XX directly yields the desired desA-androst-9- XXIV - XXVI are triethanolamine and quinoline.

1 cially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of Formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysisof a salt of a compound of Formula As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of Formula X XVI involves two separate chemical attacks; one 'being the elimination of the ll-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound of Formula XXVI. This elimination yields a A -seco acid of the formula XXVIA The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of Formula XXVIA. Preferably, a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alaknoic acid) with an alkali metal or an alkaline earth metal, for exmple, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected the A -seco acid product of Formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of Formula XXVI to compounds of Formulas XII, XV and XVI.

After the above-described ll-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of Formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of Formulas XV and XVI to isolate by forming the disemicarbazone (desA-preg-9 -ene-5-one semicarbazone substituted in the 20-position with semicarbazono) of the pyrolysis product 1 19 Y and then. regenerating therefrom the desired 5,2.0-dione of Formulas XV and XyI, or if the 20-oxo group has been protected,'for example, by reduction to a 205hydroxy moiety, by forming the semicarbazone at the -position and then regenerating therefrom the desir'edlS-bne compound.

In yet another embodiment of this invention starting was material ll-hydroxy steroids of Formula XXIVcari be directly subjected to an, oxidative ring opening, of the A-ring by ozonolysis or treatment with hydroxide peroxide, as decribed above for the oxidative ri n'g opening. of the A- ring of a compound of Formula XVII- to acompoundofFormula XVIIIa ThisoXidative ring opening of 'the A-ring of.a compound of Formula mlV-yields an 1 l-hydroxy-5-oxo-3,5-seci-A-norandrostand oic acid 3',1 1}

oic acid 3,'l1slactone of' the formula wherein X and Z have the same meaning as above.

Treatment of the 3,11-lactone of Formula XXVILwith an alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Without isolati'omt'his saltcan then be subjected to pyrolysis yielding a rnixture of an 1l-hydroxy-IOa-desA-andrOstan-S-One and an llhydroxy-lOB-desA-androstan-S-One or a mixture of an 11- hydroxy-u-desA-androstan-5-one or a mixture of an XXVII 7 1l-hydroxy-IOa-deSA-pregnan-S-One and an ll-hydroxy- IOB-desA-pregnan-S-one, as illustrated below:

XXVII alkali metal salt wherein in Formulas XXVII I .a'ndXXIX, X and Z have the same meaning as above. I

This pyrolysis of an alkali metal salt derived from a compound of Formula XXVII can be effected under the same.

conditions as described above for the pyrolysis of a compound of Formula XVIII to compounds of the Formulae XIX and XX. Though either the IOB-compound of Formula XXVIII or the wot-compound of Formula XXIX can vert the ll-hydroxy group to a leaving group in the 1'1 -p osi'tion."ThisIesterificationban be effected with the sameacids or acid derivatives and in the'same manner as described above for the esterification of a compound of Formula XXIV to a compoundof Formula XXV. As in that instance, it is also preferred in the present instance 'to form a mesoxy leaving groupin the 1l-position, though,

of course, other leavinggroups as described above are' useful for the instant purpose. Thereis thus obtained a compound of the formula. r

XXX

wherein X, Z and .LO have theYs'a-ine meanings as above.

The leaving group. can then be eliminated-from the 11- position ofa compound of Formula XXX resulting in a direct formation of adesA-androst-9-en+5-one or a desA- pregn-Q-en-S-Onejof Formulae XILXV, XVI. This, elimination can be effected by any conventional elimination meansJt is suitably conducted: under alkaline conditions in an anhydrous organic solvenLPreferably, it is effected by heating, i.e. at a temperature between about room tern perature and the reflux temperature: of the reaction mixture. Thus, treatment of a compound of Formula XXX with either an inorganic or organic base results in the formation of the desired compound of Formulae XII, 'XV,

XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (eg. a lower alkanoic acid). with an alkali metal or an "alkaline earth metal; for'e'xample, sodium acetate, potassium acetate, or the 1ik6gJASil1di'l cated, the elimination is suitably conducted inan anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.gj. dimethyl formamide, lower alkanoic. acids, e.g. acetic acid, or thexli'ke. aproton accepting solvent, such asdimethly formamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e.. if the solventis basie then the elimination can be conducted without the addition. of a sepa- V rate basic material.

In another aspect, compounds of Formulam can be prepared from compounds eof-the formula L'tMH XXXA wherein X, Z and have the same meanings as above.

The compounds of Formula XXXV can be prepared from corresponding ll-hydroxy compounds by esterification as described above for the preparation of compounds of Formula XXV. from compounds of Formula XXIV. The compounds of Formula XXX can be prepared from compounds of Formula XXXA'inthe same manner that compounds of Formula XXX are prepared from compounds of FormulaXXV, i.e. by oxidative ring opening of the A-rin-g of a. compound of Formula XXXA followed by eliminationof the residue of the A-ring to yield a compound of Formula XXX. The oxidative ring opening of the compounds of Formula XXXA can be performed by ozonolysis as described above for conversion of a compound of Formula XXV to a compound of Formula xxx:

wherein X, Z and LO havethe same meaning as above.

A compound of Formula XXXB can then be converted to'a compound of Formula XXX. This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of a compound of Formula XIXB to a compound of Formula XIX. The compounds of Formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 913,10a-steroids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between C-6 and -7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,6-dicyanobenzoquinone, according to known methods. Thus, for example, a 9B,-10a-progesterone of Formula IV wherein X is hydrogen or lower alkyl can be converted to a 95,100:- pregna-4,6-dien-3,ZO-dione.

A further embodiment of this invention comprises the preparation of 9/3,l0ot-steroids of Formulae I-V containing an ll-hydroxy s'ubstituent. This can be effected by utilizing an 11-hydroxy-lOa-desA-andrOstan-S-One or 11- hydroxy-IOa-deSA-pregnan-S-one of Formula XXIX or an 1l-hydroxy-l0 8-desA-androstan-5-one or ll-hydroxy- IOB-desA-pregnan-S-one of Formula XXVIII as the starting materials. It is preferred in this embodiment to use the 1018-isomers of Formula XXVIII as starting materials. As a first step in this the ll-hydroxy group of the compound of Formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the so'-obtained ll-esterified hydroxy compound then yields an ll-(esterified hydroxy)-desA-androst-9-en-5-one (i.e. a compound of Formula XII containing an ll-esterified hydroxy moiety) or an ll-esterified hydroxy-desA-pregn-9-en-5-one (i.e; a compound of Formulae XV- XVI containing an lla-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of Formula XIX or XX to a compound of Formula XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula XXXI wherein X and Z have the same meaning as above, and E0 is an esterified hydroxy group as described above in this paragraph,

22 yields an ll-esterified hydroxy-desA-9;8,IOB-androstan-S- one or ll-esterified hydroxy-desA-9B,l0B-pregnan-5-one, of the formula v XXXII wherein X, Z and E0 have the same meaning as above.

This hydrogenation'can be conducted in the same manner as described above for the hydrogenation of a compound of Formulae XII-XVI to a compound of Formulae VII, X, XI. Also, compounds of Formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing a 17,3-hydroxy, 17a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of Formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of Formula XXXII, i.e. wherein E0 is hydroxy.

Condensation of the so-obtained compound of Formula XXXII or the corresponding 17/3-hydroxy, 17a-1OW61 alkenyl or lower alkynyl compound (i.e. a compound of Formula VI containing a free or ll-esterified hydroxy group) then yields the desired end-product 9fl,10a-steroid of Formulae I-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of Formulae I-V from a compound of Formulae VI-XI. The so-obtained 95,10u-steroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an ll-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the 11-hydroxy group can be oxidized by methods known per se to yield corresponding l1-oxo steroids analogous to compounds of Formulae I-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees Centigrade. The Florisil adsobent used infra is a synthetic magnesia-silica gel available from the Floridin Company, PO. Box 989, Tallahassee, Fla. (of. p. 1590, Merck Index, 7th edition, 1960). 200 mesh material was used. The moiet designated by tetrahydropyranyloxy is tetrahydro-Z-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at 0 C. throughout this application when compounds of the pregnane series are referred to it should be understood that it is compounds of the 17,8-pregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17,8-series.

EXAMPLE 1 A solution of 3.2 g. of l7a-ethyltestosterone in 50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at =70 (acetone-Dry Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 0-5 Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2 N sodium carbonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline 170 ethyl- 175 hyd'roxy-5-oxo-3,5-seco-A-norandrostan-3 oic acid was filtered, washed with water and dried. Upon being recrystallized from acetone, it melted at 1965-197.

EXAMPLE 2 A solution of 1.5 g. of l'lit-ethyhl7fi hydroxy-5-oxo- 3,5-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titrated with 2 N sodium methoxide to the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17wethyl 17/3 hydroxy-5-oxo-3,S-seco-A-norandrostan+3-oic acid. 5 g. of sodiumphenylacetate was added to the residu'e, and the mixture pyrolyzed in vacuo 0.1 min.)

at 285-295", for 2.5 hours. The sublimate w s dissolved The resultant syrupy residue was chromatographed on a 60 g. Florisil (adsorbent) columniThe fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and gave Hot-ethyl-17;8-hydroxy:10a-

desA+androstan.-5-one, .M.P. 94-95"after recrystallization from petroleum ether. The fractionsv eluted with. 2 perin acetone, filtered'and the filtrate concentrated in vacuo:

cent and 5 percent ethylacetate in benzene were combined and gave 17a-ethyl-l7fl-hydroxy-10,8desA-androstam5- A one, M.P. 185-185.5-, after two recrystallizations from petroleum ether.

EXAMPLE 2A To a solution of 100 mg. of l7otsethyl=-1.7e-hydroxy- 10,6-desA-androstan-5-one in 10 ml. of absolute ethanol was added one equivalent' of sodium .ethoxide dissolved in 5 ml. of absolute. ethanol. This reaction mixture was with glacial acetic acid, poured in waterand extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatography .showed'the" maintained at room temperatureovernight, then acidified product to be 17a-ethyl-17B-hydroxy l0a-desAeandrostan-- 1 ether'and melted at 89-95. V

' EXAMPLE 3 5-one. It'was obtained crystalline from petroleum ether:

1.13 g. of 17a-ethyl-17B&hydroxy-10a-desA-androstan- 5-one was dissolved in 120 ml.,of anhydrous ether (or 1.13 g. of IOfl-isomer was dissolved in 300 ml..of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromicacid in acetic acid were, added. This was followed by the dropwise addition dur ing five minutes of 0.684 g. of bromine dissolvedin 2 ml. 7 of acetic acid. This addition was synchronized with/the decoloration rate of the reactionmixture,Immediately after this, 5' ml.'of a saturated solution of sodium bisulfite and 5 ml. of 2 N sodium carbonate solution'were added. The mixture. was then transferred into a separatory funnel, 500 ml. of ether added, shaken and separated. The

ether part was washed with water, dried and evaporated. Theres ultant bromides were dis-solvedin 100 ml."of.di-.

methylformamide, and after addition. of 3 g. .of lithium carbonate, the solution was heated at 100 for min utes. After cooling, it was'poured into one liter ofether;

24 I XAMPLE 4 Asuspension 'of 262 mg. of 5 percent'rhodium on alumina catalyst in a mixture of 26 ml. of '95 percent ethanol and 5.25 ml. of 2 sodiumhydroxide solution was pre-reduced (i.e. hydrogenated at room temperature and atmospheric pressure). To this was added .a solution of 262 mg. of 17ix-ethyl-1.7/3-hydroxy desA-androst-9-en- 5-one in 15 ml. of 95 percent ethanol, and the mixture 1 then hydrogenated at atmosphericv pressure and room temgave first crystalline fractions; whichswere followed by non-crystalline fractions The non-crystalline fractions were dissolved in 100 ml. of methylene chloride, and after the addition of 2.5 ml. of 2 percent CrO in 90' percent acetic acid, stirred overnight.The excessofchromic acid was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfiteasolution,

followedby washing with 2 N Na O solut-ion-and then with water. It was then dried and evaporated in vacuo. The

residue was dissolved. in ml. of anhydrous ethanol con taining 172 mg. of. sodium ethoxide; and left'overnight. The next day after addition of 0.5 ml. 'of'glacial acetic acid, the solution was evaporated in vacuo,;.and. the'residue was taken upin 1 liter of ether. The ether solution was washed with '2 N Na CO solution, then with water, dried" and. evaporated. The residue was chromatographed on Florisil (adsorbent) column .and gaveerystalline 17aethyl 17e-hydroxy-desA 9p,10-androstan-5 one identical (by thin layer chromatography) with the crystalline materialobtained in the first chromatographic separation.

After two recrystallizations from ether, it'melted' a142- 144; [ah-, '-1'I;65 [methanol, 1c.- :l.245fpercent].

EXAMPLES To a solution of 132 mg. of l7e-ethyl-17B-hydroxydesA-9/8,IO/S-andrQstan-S-Qne in 12.5 ml. of absolute. ethan01 containing 34 mg. of sodium ethoxide, 0.15 ml. of

' freshly distilled, .methylvinyl ketonev was added. The. re

Washed with water, 1 N hydrochloric acid, 2 N sodium carbonate, water, dried and evaporated. The residue Was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the soformedrrnixture heated 10 minutes at It was-then poured into one :liter of 'ethylacetate and the resultant.

solution washed with saturated sodium bicarbonate, then r with water, dried and evaporated: The residue was'chro matographed on Florisil (adsorbent) column.'The frac:

tion with benzene and /2 percent ethylacetate inbenzene gave regenerated starting material; Fractions with land 2 percent ethylacetate in benzene gave: 17a ethyl117flhydroxy-desA-androst-9 en-5=one, which after snblima tion (140 and 0.1 mm. Hg vacuum), was obtained as a glass. [01.113 .--36.6 (c.=1, CHCI action mixture was then, refluxed for two: hours in a nitrogen atmosphere. After cooling the reaction mixture, 0.1 ml. of glacial acetic acid was added thereto and theiresultg ing mixture was then poured into liter of ether. The resultant ether solution was washed with water, dried'over' anhydrous. sodium sulfate and evaporated in vacuo. The

residue was chromatographed on fluorescent silica-gel. plates, with the solvent system, 60 percent ethyl acetate- 40 percent heptane. The fluorescent part of the layerswas:

extracted with ethylacetate The" residue.bbtainedjaitef evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time'from pure ether,

yielding 17'ot-ethyl-9fi,ilk-testosterone, 'M .P'. 1131L-l35.". XA PLE-,6 1

A solution of 6.4 g. of .11a-hydroxyprogesterone in ml. of ethylacetate and 50 m1. of methylene chloridewas treated with ozone at -70 u'n'tit the solution beca-me blue in color. Oxygen was then passed through and the solution I evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100' ml. of glacialacetic acid, and after the addition of 5 ml. of 30' percent hydrogenv peroxide, left for 2 4 hours at 2 (in an ice box). The,

solution was then evaporated in vacuo, and. the residue triturated with ether yielding crystals. Recrystallization nane-5,20-dione-3-oic acid 3,11-lactone, MLP. 253-256". [a] +193.3 (c.=1, in. chloroform). V

25 EXAMPLE 7 a c.p.s., downfield from TMS'at 60"mc;/sec. FurthereIutiQn I of the column with" percent. ethylacetate in". benzene yielded crystalline 11a hydroxy 1OB-desA-pregnane-SJO- dione which was recrystallized from nieth'yleneichloridepetroleum ether, M.P. ISO-152; [51 -{84.0 (c.:-'O.5 in absolute ethanol).

EXAMPLE 8 To a solution of 100 mg. of methane'sulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of lloeh'ydroxy-1OB-desA-pregnane-S,20 dione. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water (100 ml.) and extracted with chloroform (3X 150ml.) and methylenechloride (100 ml.). The combined organic extracts were-washedwith water, 1 N hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from ether, giving 1lot-hydroxy-1Ofi-deSA-pregnane-S,20-dione methanesulfonate, M.P. 139-140"; @1 -f-4 6 (c.=0.5 in absolute ethanol). I I I A solution of 200 mg. of 11a-hydroxy-10B=desA-pregnane-5,20-dione methanesulfonate in' 50 ml. ofdimethylformamide was refluxed for eight hours and *then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution with 2 percent ethylacetate/benzene and-evaporation of the "eluan't' yielded desA-pregn 9 ene-5,20-dione in the form-of colorless needles, M.P. 111-113". It was shown by mixed melting concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude l1umesoxy5,20-dioxo-3,S-seco- A-nor-pregnan 3-oic acid. After recrystallization from acetone-petroleum ether, M.P. 152-1532 [0:] +479",

(c.=1, chloroform).

" EXAMPLE 12 A solution of 6g. of 11u mesoxy-5,20-dioxo-3,5-seco- A-norpregnan-3-oic acid in 150 ml. of methanol was mixed with a'solution of 1.5 g. of sodium carbonate in 55 mlfiof water. The mixture was then transferred into :11 liter sublimation flask, andevaporated to dryness. To thethus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by point to be identical with asample of the same compound prepared as described in Example 12.

' EXAMPLE 10 V To a solution of 20 g. of 1lot-hydroxy-progesterone in 150 ml. of pyridine maintained at 0, there wasadded 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at 0.=It=was then dilutedfwith a large excess of water and extracted with chloroform. The organic extracts were washed with -;2 N;hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue vwas recrystallized from methanol to give l1a-mesyloxy-progesterone, M.P. 159.5-160; [04 +1456 (c.=1, chloroform).

EXAMPLE 11 I A solution of 12 g. of 1la mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at -7 0 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture 'for five minutes. Methylene chloride was then removed u'nderreduced pressure,-and the solutiondiluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture'was then allowed to stand overnight at 2 (i.e., in the refrigerator), then evapochromatography on a 40 g. silica-gel column (benzene eluant) gave crystalline desA-pregn 9 ene-5,20-dione; M.P. Ill-113 (after recrystallization from ether).

[ah- -+56.8 (c.=0.25 percent in methanol).

EXAMPLE 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0". It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhdyrous sodium sulfate and evaporated in vacuo, yielding a colorless oil product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo.

' The residue was chromatographed on a silica-gel column and the eluates with 5 percent ethyl acetate in benzene, after concentration gave crystalline 20/3-hydroxy-desA- pregn-9-en-5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, M.P. 122123; ----33 (c.=0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of 20fi-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added 1 ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2 N aqueous sodium carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed ona silica-gel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was 20fl-hydroxy-lOu-desA-pregnan-S-one, M.P. 107-108 after recrystallization from methylene chloride/petroleum ether. R.D. methanol); [@1500 25.3, -[t1]40o 89; lum- 1305 21 1300 Further elution yielded 20/8 hydroxy 919,10y3-desA- pregnan-S-one as a colorless oil. R.D. (in methanol); 1500 1400 1350 1310 +2148.

EXAMPLE ,15-

arena 'A suspension of 262 mg; ofpercent rhodium on alumina catalyst in a mixtureof 2 ml; of 3 N aqueous hydrochloric acid and 18 ml.' 95 percent ethanol-was hydrogenated at room temperature and'atmospheric pres-- sure. A solution of 262 mg. of ZOB-hydrOXy-desA-pregn- 9-en-5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, andthe reaction mixturewas then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was crystal. 'Ihe crystals are'then recrystallized from ether givin'g'f'fla acetoxy '-1 1a, hydroxy-progesterone. 17aacetoxy-llwmesoxy progesterone is, prepared by treatmenwef l-7ii#acetoxy-lla hydroxyprogesterone with methane'sulfo'nyl chloride, according to the procedure of Example 10. i

EXAMPLE l8 3 separated by filtration, and the filtrate neutralized with t 2 vN aqueous sodium hydroxidesolution An excess of 5 ml. of 2 N aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanolawas, then removed by evaporation at reduced pressure, and after addition of 1, ml; of glacial acetic acid, it wasextracted with 1 liter of ether. The extract was washed withy2 aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the eluant. 'The'first fractions of the eluate yielded, upon concentration, 20,8- hydroxy-IOa-desA-pregnan-S-One. From the immediately subsequent fraction, fi-hydroxy-9B,lOfi-desA-Pregnan- S-one was obtained. Both products were identical with the same compounds obtained in Example 14.

EXAMPLE l6 20/8-hydroxy-9B,10a-pregn-4-en-3-one is prepared by condensation of 20,8-hydroxy-9/3,1OB-desA-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5; The product melts at 1765-1785"; 1

- 143 (chloroform).

EXAMPLE 17 A medium is prepared of 20 g, of Edamine enzymatic digest of lactalbumin,3 g. of corn steep liquor and 50 g. 'of technical dextrose diluted to 1 liter with tap water. and adjusted to a pH of 4.3-4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricansr minus strain (A.T.C.C. 6227b) and incubatedfor 24 hours at 28.using a rate of aeration and stirring such that the oxygen uptake is 6.3-7 millimoles per hour' per liter of Na SO according to the method of Cooper 'et al.,

Ind. Eng. Chem., 36, 5,04 (1944). To this medium conw taining a 24-hour growth of Rhizopus nigricansminus strain, 6" g. of 17a acetoxy-progesterone in'150 of acetone is added. The resultant: suspension of the steroid in the culture is incubated under the same conditions of temperature and aeration for an additional 24-hour period after which, the beernand mycelium are extracted,

The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume f;

to mycelium, extracted twice, each time. with a volumeof t methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride ex? tracts including solvent are then added to the'beerfiltrate; e, The mixed extracts and beer filtrate are then extracted 7 successively with 2 portions of 'methylene chloride; each portion being /2 the volume of the mixed extracts and beer filtrate, and then with 2 portions of methylene chloride, each portion being A the volume of the mixed;

extracts and beer filtrate. The combined'methylene chlo ride extracts are then washed with 2 'p0rtions,of a-2 percent aqueous solution of sodium bicarbonate, each portion being 44 the volume of the combined'rnethylene chloride extracts.:The' methylene chloride extracts are then dried with about 3-5 g. of anhydrous sodium sulfate per liter of solvent, and then, filtered. The isolvent is then removed from thefiltrate by distillation, anduthe residue is dissolved in a minimum of methylene chloride,

filtered and the solvent evaporated from the filtrateJThe resulting crystals are thendried and washed five times, each time with a 5 m1. portion of ether per gram of pregnanfli oicfacidis prepared by fozonolysis of 17aone is prepared. from 17a-acetoxy-Z0,6-hydroxy-desA- pfegn-Q-en-S-one by, hydrogenation under acidic condi- 3 tions-in'the presence of a rhodium catalyst, according to themocedure cf Example 15.

i L EX PL 22 e f17at-acetoxy-2()p-h d i /.9 P 413m} one" is,

I prepared by condensing methyl vinyl ketone with 17a-ace toxy-ZOB,10l3 hydroxy 9fi-desA-pregnan 5-one according to the procedure of Example 5 except instead of conducting the condensation :in" absolute ethanol and catalyzing it with-sodium ethoxide, thecondensation is conducted in acetic-acid. and-is catalyzed with p-toluene sulfonic acid.

20 3;hydroiiy-4;methyl9;9,10a-pregn-4-ens3wne is preparedjby condensing ZOfi-hydroxy-fiu,lOfidesA-pregahone and @ethyl (vinyl ketone according ,to the procedure 'of' Example 5. i

V L AMPL 24 l7 9-hydroxy-j oxo-3,5-secoeA-nor-androstam3-eic acid is prepared'by ozonolysisof testosterone according to, the

procedureof Example 1*.* 7 7 I EXAMPILEZS r r V droxy-IOB desA-andrmtan-Smne are prepared from 17 3- hydroxy-5 oxo 3';5-sec0 A-norandrostan 3 oic' acid by conversion-of the latter to its sodium salt followed by ccord ing to the procedure of Example' 2. V "'EXAMPLE26 I 17p-hydroxy-desA-androsbQ-en-ionesis prepared from 17fi-hydroxy-10a-desA-androstamione by bromination followed by' 'dehydrobromination, according to the proce-, dure of Example 3.

,Des'A-and'rost-9-ene-5,17-dione; is prepared from. 1718- hydroxy-desA-androst-9-en-S-one by oxidation of the latterwith a: 2 percent chroniic acid solution in percent pyrolysi acetic acid-.The soaobtained desA- androst-Q-ene-S,l7 di+ A solution of 236 mg. of 17,8 hydroxy-desA-androst-9- en-S-one iI JAQml QSper ent ethanol and. 5.25 ml. .2 N 7 aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced percent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue l7fi-hydroxy-9fl,10fldesA-androstan-S-one was obtained by crystallization. M.P. 144.5-145"; -22 (c.'=0.103; dioxane). The 17B-acetate (i.e. 17B-acetoxy-9B,IOB-desA-androstan-S- one) is obtained by acetylation of testosterone followed by ozonolysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and 27 respectively, and melts at 118-119"; -28 (c.==().103; dioxane).

EXAMPLE 28 To a solution of 282 mg. of 17B-hydroxy-9B,10/3-desA- androstan-S-one 5-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction'mixture then stirred overnight. The reaction mixture was then washed with percent aqueous sodium hydrogen sulfite,'2 N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 9,9,10fi-desA-androstane-5,17- dione 5-mono-ethylene ketal. Splitting of the ketal inacctone solution in the presence of a catalytic amount of ptoluene sulfonic acid gives 9 3,IOB-desA-androstane-S,17- dione which melts, after recrystallization from cyclohexane, at 775-78; [06113 +55 (c.=0.107; dioxane).

EXAMPLE 30 To a preformed solution of one mole equivalent of prop-1-inyl lithium in 100 m1. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9B,IOB-desA-androstane-S,17-dione S-mono-ethylene ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anyhdrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave 17a-(prop-l-inyl)-17fl-hydroxy-9fi,10fl-desA- androstan-S-one.

EXAMPLE 31 17a- (prop-1-inyl)-17,B-hydroxy-9,8,10a androstan 4- en-3-one is prepared by condensing methyl vinyl ketone with 17m- (pr0p-1'-inyl) -17fi-hydroxy-9,B, 10fi-desA-androstan-S-one according to the procedure of Example 5. The product melts at 164-165 EXAMPLE 32 To a stirred solution of one mole equivalent of 2-methyl-prop-2-enyl magnesium bromide in 100 ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9,8,IOB-desA-androstane-S,17-dione 5-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an icesalt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of p-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. From the residue 17w(2'-methyl-prop-2'-enyl)-17B-hydroxy-9fl,10;3 desA- androstan-S-one was obtained. I

EXAMPLE 33 1704 (2 methyl prop 2' enyl) 17;? hydroxy- 9,8,lOa-androst-4-en-3-one is prepared from 17a-(2-methyl-prop-2'-enyl)-17B-hydroxy-9;3,10 3-desA androstan 5- one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The product melts at 106108.

EXAMPLE 34 a acetoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared by acetylation of 160: hydroxy-20-ethylenedioxypregn-4-ene-3,20-dione with one equivalent of acetic arihydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. 16aacetoxy-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3- oic acid is prepared by ozonolysis of l6a-acetoxy-20-ethylenedioxy-pregn-4-en-3-one according to the procedure of Example 1.

EXAMPLE 35 1606 acetoxy ZO-ethylenedioxy-10a-desA-pregnan-5- one and 16a-acetoxy-20-ethylenedioxy-10,8-desA-pregnan- 5-one are prepared from 16ot-acetoxy-20-ethylenedioxy-5- oxo 3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

EXAMPLE 36 16a acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one is prepared from 16u-acetoxy-20-ethylenedioxy-IOrx-desA- pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 37 160: acetoxy-ZO-ethylenedioxy-9/3,IOB-desA-pregnan-S- one is prepared from 16a-acetoxy-20-ethylenedioxy-desA- pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

EXAMPLE 38 160: hydroxy 20-ethylenedioxy-9/3,10a-pregn-4-en-3- one is prepared by condensing 16u-acetoxy-20 ethylenedioxy-desA-9fi,IOB-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5.

EXAMPLE 39 3B hydroxy 16a-methyl-pregn-5-en-20-one ethylene ketal is prepared by ketalization of 3B-hydroxy-16a-methyl-pregn-5-en-20-one in benzene solution with ethylene glycol using p-toluenesulfonic acid as catalyst. Pyridinechromic acid oxidation of the so-obtained Tap-hydroxy- 16a-methyl-pregn-S-en-ZO-one ethylene ketal yields 16amethyl 20-ethylenedioxy-pregn-4-en-3-one. 16u-methyl- 20-ethy1enedioxy-5-oxo-3,5-seco-A-norpregnane-3-oic acid is prepared by ozonolysis of 16a-methyl-20-ethylene-dioxy-pregn-4-en-3-one according to the procedure of Example 1.

EXAMPLE 40 1606 methyl-20-ethylenedioxy-10a-desA- regnan-S-one and 16u-methyl-20wthylenedioxy-IO/B-desA-pregnan-S-one are prepared from 16a-methyI-ZO-ethylenedioxy-5-oxo-3,

-seco-A-norpregnan-3-oic acid by conversion of the 'latter to its sodium salt followed by pyrolysis, according to theprocedureof Example 2.

EXAMPLE 41.

16a methyl 20-ethylenedioxy-desA-pregn9-en- 5-one is prepared from 16a-methyl-ZO-ethylenedioxy-10u-desA- pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42 i 7 16a methyl-20-ethylenedioxy-9B,IOB-desA-pregnan-S- one is prepared from 16a-methyI-Z0-ethylenedioxy desA- pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

EXAMPLE'43 7 16oz methyl--ethylenedioxy-9fi,10ot-pregn-4-en-3-one is prepared by condensing 16a-methyI-ZO-ethylenedioxy- 9/3,IQ S-desA pregnanPS-One with methyl vinyl ketone, ac-' cordingto the procedure of Example EXAMPLE 44- 21 acetoxy-l1a-hydroxy-20-ethylenedioxy-pregn-4-en- 3- one is prepared by microbiological treatment of-2 l-acetoxy-20-ethylenedioxy-pregn-4-en-3-one, according to the procedure of Example 17. 21 Acetoxy-lM-mesoxy-ZO- ethylenedioxy-pregn-4-en-3-one is prepared by treatment of 21-acetoxy-1 1a-hydroxy-20-ethylenedioxy-pregn-4-ene- 3-one with methanesulfonyli chloride, according to the procedure of Example 10.

EXAMPLE 4s 21 acetoxy 11a-mesoxy-20-ethylenedioxy-5-oxo-3,5-

seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 21 9 acetoxy 11a-mesoxy-Z0-ethylenedioxy-pregn-4-en-3- one, accordingto the procedureof Example 11; i

7 EXAMPLE 46 n 21 acetoxy-20-ethylenedioxy-desA-pregn-9-en-5-one is prepared from 21-acetoxy-2O-ethyleriedioxy-1lit-mesoxy f 3,S-seco-Amorpregnan-B-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12, except that the crude product is reacetylated by treatment with acetic anhydride/" pyridine prior to its being worked up.

EXAMPLE 47 21 acetoxy 20 ethylenedioxy-9fi,lOB-desA-pregnan 5 one is prepared from 2leacetoxy-ZO-ethylenedioxydesA-pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

EXAMPLE 48 V 21 hydroxy 20 ethylenedioxy 9/3,l0e-pregn-4-enthe procedure of Example 5.

' desA-pregnan 5 one-is prepared from 2011 hydroxy 32. EXAMPLE 51 a J 16a,17a isopropylidenedioxy-desA-pregn 9- en-5,20- dione is prepared from 5,20 dioxollwmesoxy 1 6cc,

17.e-isopropylidenedioxy-3,5secwA-norpregnanG-oicacid by conversion of the latter to its sodium salt, followed by pyrolysis according to the'procedure of Example 12.

7 EXAMPLE s2 7 20s hydroxy 16:1,1703 isopropylidenedioxydesA pregn 9 en 5 one is preparedfrom 1611,17ot-i80 propylidenedioxy-desA-pregn-9-ener5,ZO-dione by reduction and reoxidation, according to the procedure of Ex ample 13. 7

EXAMPLE 53 20B hydroxy l6zx,l7ea isopropylidenedioxy 95,105-

16OL,170L isopropylidenedioxy-desA-pregn 9 en-S-one by hydrogenation. according to the procedure of Example 14. 7

EXAMPLE 54 20,8 hydroxy 160:,17wisopropylidenedioxy-fi fi,10a!' pre'gn 4 en 3 one is prepared by condensing methyl 3-one is prepared from 2l-acetoxy-20 ethylenedioxy-9fl,

lOfl-desA-pregnan-S-one by condensing the latter with methyl vinyl ketone, according to the procedure of E "ample 22." a

EXAMPLE 49 i 11a mesoxy 1604,17ot' isopropylidenedioxy-progesterone is prepared by treatment of 11 0: -"hydroxy -'1 6u, 17otisopropylidenedioxy-progesterone With methane sul-.

fonyl chloride, accordingto the procedure of Example EXAMPLE 50 5,20 dioxo- 11a mesoxy- 16.1.17 isopropyliden'e dioxy 3,5 seco A-norpregnan-oic acid is preparedby ozonolysis of 11a, mesoxy l6ot,l7oc-isopropylidenedioxy-progesterone, according to the procedure of- Ex-' ample .11. i

vinyl ketone with 205 hydroxy 16a,17aisopropylidenedioxy-desA 95,105 pregnan 5 one according to EXAMPLE :,17 cc dimethyl 175 hydroxy 5 7 oxo-3,5-'seco-A- n'orandro'stan 3-oie acid is prepared from 7'a,l7a-'dimethyl-.

testosterone by ozonolysis of the latter, according to'the, procedure of Example 1.

; EXAMPLE, 56

70,l7et dimethyl 17 B hydroxy IOadeSA andmstan- 5 one and 7a,17a dirnethyl 17;? hydroxy 10B'-desA androstan-S-one are prepared from 705,17OL dimethyl-l7fl hydroxy 5 oxo 3,5- seco-A-norandrostan-oic acid by conversion of the latter to its sodium salt'ffollowcd by pyrolysis, according to the procedure of Example 2.

EXAMPLE s7. 7

70,17ec dimethyl 17,8 hydroXy-desA-androst-9-en- 5-one is prepared. from 700,170: dimethyl 17B hydroxy desA-androstan 5 one by bromination followed i by dehydrobromination, according to the. procedure. of.

A 711,170; dimethyl 9,8,10a testosterone is prepared from 7 170 dimethyl' 17,6 hydroxy desA 95,10 8

androstan 5 -one by condensing the latter with methylvinyl ketone, according to the procedure of Example 5.

, EXA PLE 6,0

11a mesoxy 17 methyl-progesterone is prepared from 111x hydroxy 17oz methyl-progesterone by treatment of the latter with methane sulfonyl chloride, accord. V

ing to the procedure of Example 10; i V

EXAMPLE 61 11a mesoxy 17a methyl 5,20-dioxoj- 3,5 seco Anorpregnan-3-oic acid is'preparedfrom Ila-mesoxy- 17 a methyl-progesterone by ozonolysis of the latter, ac-

cording to the procedure of Example 11.2

EXAMPLE 6 2' p 170: methyl 'desA-pregn 9 i ene 5,20 -dione is prepared from mesoxy- 17a methyl- 5,20 dioxo-i 33 3,5 seco-A-norpregnan 3 oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

EXAMPLE 63 2018 hydroxy 17a methyl-desA-pregn-9-en-5-one is prepared from 170: methyl-desA-pregn 9 en-5,20-dione according to the procedure of Example 13.

EXAMPLE 64 20B-hydroxy-17a-methy1-9B, IOfl-desA-pregnan-S-one is prepared from l7a-methyl-20;3-hydroxy-desA-pregnan-9- ene-S-one according to the procedure of Example 15.

EXAMPLE 65 20B hydroxy 17a methyl-9B,10u-pregn-4-en-3-one' is prepared by condensing 17a-methyl-20fi-hydroxy-9B,10B- desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 4.

EXAMPLE 66 A solution of 12.8 g. of l7a-methyltestosterone in 200 ml. of methylene chloride and 100 ml. of ethyl acetate was ozonized for 1 hour and 5 minutes at -70 (acetone- Dry Ice bath) until a blue color developed.-After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 400 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material 17,8- hydroxy 17 on methyl oxo-3,5-seco-A-nor-androstan- 3-oic acid. After recrystallization from acetone-hexane, it melted at 195-197, '[oc] =9.8 (c.=1.0 'in chloroform).

EXAMPLE 67 A solution of g. of 17 3-hydroxy-17a-methyl-5-oxo- 3,S-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2 N sodium carbonate solution, and again'with water, dried and evaporated. This gave a sirupy residue, which by thin layer chromatograms and infrared spectra consisted of 17fl-hydroxy-17umethyl-l0a-desA-androstan+5-one as the major and 175- hydroxy 17oz methyl 10,8 desA-androstan-S-one as the minor product. v

Three additional pyrolyses were performed as described above, and the combined products so-obtained was chromatographed on a 850 g. silica gel column, using 5% ethylacetate in benzene as the eluent. This chromatography yielded 17 8-hydroxy 17a methyI-IOa-desA-androstan-S-one, which after recrystallization from petroleum ether melted at 96 97, [oz] =28.2. (c.=0.5 in chloroform). A I. a p I Further eluates of the column gave product, 17fl-hy-j droxy-17a-methyl-10fi-desA-androstan-5-one which, when recrystallized from ether, melted at 165-167",

(c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of 17fl-hydroxy- 17m-methyl-lOa-deSA-androstan-S-One and 17,8-hydroxyl7a-methyl-IOfl-desA-androstan-S-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 20.1 ml. of a solutionprepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of 17fl-hydroxy-l7a-methyl-10a-desA-androstan-S-one.

EXAMPLE '68 To a solution of 11.2 g. of l7fl-hydroxy-l7a-methyl- 10u-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disappearance of excess bromine. After bromination was complete, 53 ml. of 10% sodium hydrogen sulfite solution and 53 ml. of aqueous 2 N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was. then separated, washed with water, dried,.and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100 for 45 minutes. After cooling, 2 liters of ether were added and the ether solution washed with water, 1 N hydrochloric acid, and then again with water, dried and evaporated. The residue was dissolved in 200 ml. of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g. of zinc powder were added and the mixture heated for ten minutes at After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethylacetate, and washed with saturated sodium bicarbonate solution, then with water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first 17,8-hydroxy-17a-methyl-10a-deSA-andrOStan-S-one, followed by 173 hydroxy-17a-methyl-desA-androst-9-en-5-one. After recrystallization from ether, the latter compound melted at 103-104, [a] =-63.2 (c.=0.5 in chloroform).

EXAMPLE 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst-in a mixture of 130ml.- of 95% ethanol and 216 ml. of 2 -N sodium hydroxide was prereduced. Tothis was then added a solution of 1.25 g. of l7 3-hydroxy-l7amethyl-desA-androst-9-en-5-one in 75 ml. of 95%,, ihanol, and then the mixture was hydrogenated at atmospheric pressure and room temperature. After onemole equivalent of hydrogen was absorbed, the reactioniyva'slstoppcdg the catalyst was removed. by filtrationfand the filtrate evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the so-mormed mixture. then dissolved in 2 liters of ether, and'the'resultant cloudy :solu'tionwas washed with water, then driedand'evaporated: The residue was dissolved in 50 ml. of methylene chloride and oxidized with 5 ml. of 2%. chromic*acid in acetic acid until green color of .reaction mixture. :After"then being washed with sodium hydrogen sulfite solution '2 N sodium carbonate solution and.water,-' the reaction mix"- ture was dried oversodium sulfate and evaporated-The residue was chromatographed 'VCIY SIOWlY? on: a 'SO g'; silica gel column,'with :5.%:ethylac'etate1i'n benzenefand followed with thinlayerchromatography;::First, 17-B-hydroxy- 17a methyl 9a,l0a.- desA-androsta n-5-onewas. eluted. After a minor amount of:.-mixed-.-matetial', 17;; hydroxy -.17a --methyl 9 3, 10 3-desA-androstan-5 one was eluted. After recrystallization from=ether=petroleurn "ether, it melted at 94 96. 1 1

pregnan-S-one.

3s i, EXAMPLE 70 17u-methyl-9/3,wot-testosterone, is prepared from 170:-

methyl-175-hydroxy-desA-9fl, 10,8-androstan--one by 4 co ndensation of the latter with methyl vinyl ketone, according to the procedure of Example 5. The product melts at 128-190". V p

7 EXAMPLE 71 V i A section of 6 g. of 11a,2OB-diacetoxy-pregn-4-en-3- one in 100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at 70. After methylene chloride was'rerrio'ved by distillation; in 'vacuo, the residual'solu f tion was diluted to 100 ml. with ethylacetater To this 5 ml. of 30 percent hydrogen peroxide was added and left overnight at room temperature. The reactionimixture was concentrated to dryness in vacuo, the residue taken'up in 1 liter "of ether, and" the resulting 'solution extracted,

10 times with 50' ml. portionsfof 2 N aqueous sodium give oic' acid.

EXAMPLE 72 methanolicsolution of :5 g. of 1la,20,B-diacetoxy=5 oxo-3,S-seco-A-nor-pregnan-3-oic acid was treated with one-half mole equivalent of sodium carbonate, and evaporated to dryness in vacuo. Potassium acetate (5 gi),was

and 0.02 mm. The sublimate was chromatographed on a silica-gel column to give 110:,20B-di3C6t0XY-IOB-dCS A- V '7 EXAMPLE 73- V V Bromination and dehydrobromination starting with V 1la,20fl-diacetoxy l0fl-desA-pregnana5 one according to the procedure of Example 3, gave 1Ia,20B-diacetoxy-' desA-pregn-9-en-5-o'ne; y

' EXAMPLE 74 "carbonate. The carbonate extract was then acidified with ,7

ice-cold concentrated hydrochloric acid, The precipitated product was'separated by filtration, and crystallized-to l1a,2O 3-diacetoxy-5-oxo 3,5 seco-A-nor-pregnan-3- according to the procedure of Example i added to the'residue which was then pyrolyzed at "295 40 Hydrogenation of 11oi,20,8-diacetoxy-desA-pregnQ-em' S-one in ethanolic hydrochloric acid over 5 percent rho-V dium on alumina'catalyst at room temperature and at- A. was as; g. of l7a ethyl l7B-hydroxy-androsta- 1,4-di6l'1-3i0l'16flfl'75 ml.,. ofmethylene chloride and. 25 m1; :of, ethyl acetate was :ozonizedat '-70 till it became blue.:Aftencevaporzition to dryness; the residue was dissolved inr;100:ml;vof glacial acetic acid containing 5 ml; of c301; percentvhydrogen' peroxide, and set at room temperatuteyfor 2:.days.= :The-"reaction mixture was concenra edrltQudryness and the-residue "dissolved in one liter of,jetheraThepethersolution wast-hen extracted 1'0 times With'LZi ml; portions of-- aqueous 2- N sodium carbonate solutioms. and theixcarbo'nate extracts' were acidified with icecold concentrated-hydrochloric acid The" non=c"rystalline; precipitate containing 1 17a-ethyl-l7fi-hydroxyd0a carboxyadesA androstan-S-one*was "separated byfiltration anddried, .then dissolved in-1351rnl; ofabs'olute ethanol,

7 and after addition-of 9' ml. of aqueous 2*N sodium hyrd oxidgboiledfor '1 hniThereactionmixture z'waslcon centrated in vacuo to a small volume, and diluted with 1750 ml. ofether. The ether solution: was washed' with water, 7 dried over anhydrous sodium sulfate, a d: concen trated in vacuo to dryness, The residue wascry'stallized- -fro'm ether-petroleum ether, to give 17ot-fithYl-l7/3-hYr droxy-lOwdeSA-andrOstamS-Qne, 89-90",

. EXAMPLE as r 1 3 (17/3 hydroxy-5-oxo-3,5 seco-A-nor-androstan-17ayl-3-oic acid)-propionic acid 'lacto'ne is prepared by ozonolysis of 3 3 -oxo 1'7 [i-hydroxy-and-rost4enl 7 afyl V propionic'acid lactone accordingto the procedureyof Example 1;

EXAMPLE 79 H V 3 (17B hydroxy-5 -oxo-l0wdesA-androstan-17a-yl)- propionic acid lactone: and 3-l17/3hydroxy-5-oxo-l0fi% desA-androstanelh-yl)propiohiciacid lac-tone are 'pre': pared from a 3- l 7,6-hydroxy-5 oxo-3,5-seco-A-nor-andro stan-17a-yl-3-oic tacid) -propionic acid, last-one:by' converse s'i'on of-th-e latter to its sodium salt followed by pyrolysis,

3 (1 7/87 hydroxy-S-oxo-desA-androstQ-tan-Hail): propionic' acid lactone'is prepared.- from :3-(1' 7fl hyd'roxy 5-oxo-10a-desA-androstan-17a-yl')-propionic1 acid lactone by bromination followed by dehydrobromination, according to the procedure of Example;,3;., ,7

"EXAM E s1 yl)-propionic acid lactone is prepared from 34175- 13 1 'droxy-5-oxoedesA androst-9-en l7a yl)' 'propionic: acid l lactone by hydrogenation. in the presence of a rhodium catalyst, according to the procedure of Example 4;

propionic. acid acetone isprepared by condensing 3-(17i3- hydroXy 5-oxo 9fi,lllpi-desArandrostan-17a-yl) propionic acid lactone with methyl vinyl ketone, according ,tq the procedure of Example ,5." 7

XA PLE 83' l-7a,2 0 ;20,2l bis methylenedioxy 11a mesyloxypregnw4-en-3'-oneais prepared by treatment-10f17:) 20220,

ZI-bis-methylenedibxy hydroxy-pregn-4-en '3mne with methanesulfonyl chloride according to the procedure of Example 10. a

s i a 17,iz0;20,2-1;., bis methylenedioxyel rwin s iox e oxo-3,5-seco-A-norpregnan-3 oic' 7 acid is prepared by ozonolysis of, l7a,2 );20",2:l-bis methylenedioxy-Ilqunies ,loxy-pregn-4 -en-3-onei according to the procedure of Example 11L" V t I EXAMPLE..1- t

17a,20;20,21 bis in t meawarded-gagin ass one'is'prepared from 17a,20;20,2l-his-methylenedioxy,

1 lwmesyloxyd oxoo ,S-s'eco-Anorpre-gnanfl oic "acid by conversion of the latter to its sodium salt follo'wedjby pyrolysis, according to the'prbiedi re Example llr EXAMPLEse 17oz,2O;Z"0, 21' his; y ethyle icdioiif 7 9E30 'desA- presence of a rhodium catalyst according to; the procediir'e of Example 14-."

t 1 EXA r; u

17a, 2.0;20,2'l bis methylenedioxy fi lo a-pregn-ten- V V 3 -one 1s prepared byrcondensin'g 'methylvinylketonewithr V 17a,20;20,21 bis methylenedioxyr 9fi,l'05 d esAepregnanfi ione, according to the procedure ofExample;

37 EXAMPLE 88 20 8 hydroxy 95,101! pregna 1,4 dien 3 one was prepared by condensation of 20,B-hydroxy-9B,10;8- desA-pregnan-S-one with 1 equivalent of methyl ethinyl ketone in boiling benzene solution, catalyzed by sodium hydride.

EXAMPLE 89 One ml. of Jones Reagent (0.004 mole CrO is added to 200 mg. of 17,8-hydroxy-9B,IOfi-desA-androstan-S-one in 20 ml. of acetone at -l. The mixture is then left for 15 minutes at room temperature, and ml. of ethanol then added. The resulting suspension is evaporated to dryness in vacuo, water is added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which crystallizes upon the addition of a small portion of petroleum ether. The so-obtained crystals of 913,10fi-desA-androstane-5,l7-dione melt, after recrystallization from cyclohexane, at 77.5-78"; [M +55 (c.=0.107, dioxane); R.D. in dioxane (c.=0.107%): in m ([oc]- value in degrees): 550 (+70); 400 (+297); 350 (+798); 320 (+2968) max.; 300 (+467); 299 (0); 290' (1890).

EXAMPLE 90 A solution of 250 mg. of 17fl-hydroxy9fl,l0B-desA- androstan-S-one dissolved in 2.5 ml. of pyridine and 2.5 ml. of acetic anhydride, is left at room temperature for 18 hours. The mixture is then evaporated to dryness at 80/ 11 mm., the residue taken up in ether, and the ether phase washed with 1 N hydrochloric acid, sodium bicarbonate and water, and then dried over sodium sulfate. After filtration and evaporation of the ether, the residue is then treated with a small quantity of petroleum ether yielding crystals of l7B-acetoxy-9fi,1lfl-desA-androstan- 5-one which, upon recrystallization from methanol, melt at 118119; [u] =28 (c.=0.103%, dioxane); R.D. in dioxane (c.=0.103%); A in ma ([a]-value in degrees); 400 (-30); 356 (0); 350 313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (0); 280 (-652).

EXAMPLE 91 A solution of 250 mg. of 17fl-acetoxy-9fl,IOB-desA-androstan-S-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide in refluxed for 60 minutes. The resulting mixture is evaporated to dryness in vacuo, water added to the residue and the suspension extracted with ether. The ether phase is washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of 17 fi-hydroxy- 9,8,lOB-desA-androstan-S-one which upon being recrystallized from ethylacetate melt at 144.5145 [a] -22 (c.=0.103, dioxane), -R.D. in dioXane (c.=0.l03); in mg ([ot]-value in degrees); 400 (-7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492) min.; 305 (+504) max.; 300 (+324); 293 (0); 290 (-202).

EXAMPLE 92 A solution of 10 g. of 1lfi-formyloxy-androsta-l,4- diene-3,l7-dione in 100 ml. of acetic acid was ozonized at 0 until thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml. of water and the mixture was then heated to 100 for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated sodium bicarbonate solution. The undissolved material was extracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The eluates were concentrated and gave, on addition of hexane, 115 formyloxy-lOg-desA-androstane-S,17-dione, M.P. 117-1 17.5 (recrystallized from acetonecycl0- hexane), [a] =93 (dioxane).

38 EXAMPLE 93 By hydrolysis of 11 3-formyloxy-IOE-desA-androstane- 5,17-dione in 2% methanolic potassium hydroxide there is obtained 11,3 hydroxy-l0g-desA-androstan-5,17-dione, which melts at 154; [a] +96 (dioxane).

EXAMPLE 94 250 mg. of 115' hydroxy-10-desA-androstane-5,l7- dione and 250 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benzene were refluxed in a nitrogen atmosphere for 6 hours. The reaction mixture Was then I The compound, 11fl-formyloxy-S,17-dioxo-3,5-seco-A- norandrostan-3-oic acid is prepared from 11p-formy1oxy androst-4-ene-3,17-dione by ozonolysis according to the procedure of Example 11. The so-obtained product melts at 220-221; [u] +107 (dioxane).

EXAMPLE 96 3.7 g. of the sodium salt of 1lfi-formyloxy-5,l7-dioxo 3,S-seco-A-nor-androstan-3-oic and 12 g. of sodium phenylacetate are fused together in vacuo (0.1 torr). When the bath temperature reaches 220 the molten mass begins to decompose. The bath is then heated further within (30 minutes) to a temperature of 290. Once this temperature has been reached the mixture is left for another 10 minutes at the initial pressure of 0.1 torr. The distilled material is then chromatographed over 30 g. of aluminum oxide (activity grade 3). Elution with a total of 200 ml. of petroleum ether-benzene (2:1), followed by evaporation of the solvent and trituration of the residue in the presence of petroleum ether, yields desA- androst 9 ene-5,17-dione which upon recrystallization from cyclohexane melts at 123123.5; [a] =+83 (c.=0'.1021, dioxane).

EXAMPLE 97 20,8-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of 20B-acetoxy-pregn-4-en-3-one according to the procedure of Example 1.

EXAMPLE 98 A solution of 15.15 g. of 20p-acetoxy-5-oxo-3,5-seco- A-nor-pregnan-3-oic acid in 250 ml. of methanol containing 10 g. of potassium hydroxide was refluxed for 2 hours. The methanol was then removed in vacuo and the residue was dissolved in 100 ml. of water. The solution was chilled to 0 and acidified to Congo red by the addition of 20% hydrochloric acid. There was thus obtained 2018 hydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid, M.P. 181182, [a] =13 (dioxane).

A solution of 4.7 g. of ZOB-hydroxy-S-oxo-3,5-secoA- nor-pregnan-3-oic acid in 100 ml. of methanol was neutralized with 1 N sodium methylate solution against phenolphthaleine. The solution was then evaporated and the residue, consisting of 20fl-hydroxy-5-oxo-3,5-seco-A- nor-pregnan-3-oic acid sodium salt, was refluxed with 100 m1. of quinoline for 8 hours. The cooled mixture was pouredon a mixture of g. of ice and 100 ml. concentrated hydrochloric acid and extracted with ether. The ether extract was worked up and the oily residue was chromatographed on silica gel. Elution with methylene chloride gave 10u-desA-pregnane-5,20-dione, M.P. 126- 127? (crystallized from isopropyl ether), [a] =82 (dioxane). Elution with methylene chloride containing 1% acetone gave ZOB-hydroxy-10a-desA-pregnan-5-one,

MP. 104 -104.5 (crystallized from ether-hexane) [a] ='-10' (dioxane). The fractions obtained with, methylene chloride containing -l0% acetone were evap orated'and theoily residue was dissolved "in 40ml. of

acetone. The solution wastreated with 3 ml. of Jones reagent (0.004 mole CrO at and kept at the same.

temperature for '10 minutes. After the addition of 5 ml. of methanol; the solution was evaporated and the residue was diluted with water and extracted with' ether. The ether extract was worked up and gave 10a-desA-pregmane-5,20-dione.

EXAMPLE'99Q V ZOfi-hydroxy-desA-pregn-9-en-5-one is prepared from p-hydrox'y-IOa-desA-pregnan-SEone by bromination followed .by dehydrobromination, according to the procedure of Example 3. The so-ob'tained productgaften recrystallization from methylene chloride-petroleum ether, melts at 12.2-123. 1

a EXAMr Eino. I 5,20-dioxoe3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of progesterone according to the pro cedure of Example 1. e t

' EXAMPLE 101 l'Oa-deSA-Pregna 1' 5,20 dioneand IOB-desA-pregnan-z 5,20dione are prepared from 5,20-dioxo-3,5-seco-A-nor pregnan-3-oic acid by conversion of the latterto its sodiof tert. butanol water azeotrope followed by the addition of a solution of 33 g. of potasium carbonate in 80 ml. of wa a ter and 620ml. of7 aqueous sodnim:metaperiedate solw tion. To the reaction mixture there was firstaddedwi'th vigorous stirring atroom temperature, 75 ml. of 0.8% potassium permanganate and thereafter simultaneously 7 within minutes 1350 ml. of 7% sodium'metaperiodate I .solu'tionand 100 ml; of'0.8% potassium permanganate solution, Another 1080 ml. of'-7% sodi-umimetaperiodate solution and 100ml. of 0.8% potassium permanganate solution were then added within 45 minutes. The reaction mixture was thenv stirred for l bour, filtered over a filter r aid (Hyflo) and the residue was washed 'with 250 ml; of

' tertbutanol-water azeotrope. The filtrate was evaporated,

the .residue taken up in 800ml; of water and filtered. The

alkaline filtrate was chilled; to 0 acidified with cold 20% I p j e v, a hydrochloric acid and extracted with methylene chloride...

After working up, the extract afi'ordeda mixture of20aand 20dtctrahydropytany-loxyQioxoeS,5 seco-A-noi preg n'an3-oic acid as a viscous oil. This oilwa's'dissolved. in '300 ml. of methanol and neutralized with 1 Nlithium methylate. The solution was evaporated --tofdryness in vacuo. The oily residue was dissolved in=300 ofiben zene, evaporated again and dried at 111 Hg and 1.00? for Z'hours. T here was obtmnedv a, mixture ofthe lithium I salts of 2011- and 2018 tetrahydropyranyloxy-5-oxo-3 ,5-

, seco-A-nor-pregnan-3- oic acid as an amorphous powder.

um salt followed by pyrolysis, according to the procedure of Example 2. a

' EXAMPLE 102' The compound, desA -pr'egn-9-en e-5,20 dione'is" pro pared from'10a-desA-pregna-5,20 dione by bromination crystallization from ether, melts at 111-113". 7

' EXAMPLE 103 15 ml. of 0.8%"potassium permanganatesolution was 7 added to a mixture of 11 g. of 20fi-tetrahydropyranyloxypregn-4-en-3-'one, 500 mlJof an azeotropicmixture of tertiary 'butanol and water, .7 g. of potassium carbonate,

20 m1; of water and 120 ml. of 7 %sodium metaperiodate' solution with vigorous stirring at room temperature." 250 ml; of 7% sodium metaperiodate and 20 ml. of 0.8%.

potassium permanganate solution were then simultaneously added ,within 15 minutes. To'the so-obtained suspension, 220 ml. of 7% sodium metaperiodate solution.

7 7 EXAMPLE 105' p A, solution 0159 g. of '20,8 tetrahydropyranyloxy-5soxo,

' 3,5-secoA-nor-p:regnan-3-oic' acidin 100 ml. of meth .followed' by dehydrobromination according to the pro-* cedure of Example '3. The so obtained produchafterfreanol Was'neutralized with '1 'N' li-thiummethylate; solution against phenolphthaleine, followed: by evaporation in vacuo to dryness. The so-obtained residue was taken up in.

benzene, and the benzene evaporated yielding 20i3 tetralithium salt as a semi-crystallinepowder...

and, in lorde'r to keep the mixture violet in color, 15- mL. of,

0.8% potassium permanganate'solution were then added in the course of 30 minutes. The mixture was then stirred for minutes, filtered over a filter aid (Hyflo) and the residue was washed with ml. of tort. butanol-water "azeotrope. vThe filtrate was evaporated in vacuo at 50 'and the residue diluted with 150 ml. of water. The solution was acidified with cold 20% hydrochloric acid'to s got this lithium salt, 7.5 of anhydrous sodium acetate and 7.5 g. of anhydrous potassium acetate were V a mixed and pyrolyzed at 0.02-0.1n1m. Hg. and 290 for 4 hours; The distillate was. chromatographed on silica gel using methylene chloride and methylene chloride containing 0.5l-% acetone as the'elutionagents. The fractions were evaporated and gave on treatment with ether-hexane 2OB-tetrahydropyranyloxy-1o'wdesA-pregnan-fi-one, 125.5-127" (crystallized from methanol) '[oc];; -453? dioxane). a

The oily part of the evaporation residueicontaining bc- V 7 sides the latter compound thecom'pound ZQB LGHZXIIYdTQ- pyranyloxy-l0fl-desApregnan 5-one ethanol After theaddition of '10 ml. of water and 200 mg. of p-toluenesulfonic acid monohydrate, the solution was/refluxed for '60 minutes and evaporated in vacuo. The residue was tihen treated with water and extracted with ether. The ether extract was Worked up and gave 20fl-hydroxy-l0u-desA pregnan-S-one, M.P; 104.5-" crystallized from eher hexane);

EXAMPLE 106' 250 'mg. of ZOfl-tetrahydropyranyloxy-10wdesA-preg: nan-S-one was dissolved in 8 ml. of ethanol and after the addition of 1 ml. of. water and: 15 mg.. of p-toluen'esul fonie acid monohydrate refluxed for 1 houL'Thereaction I mixture was then evaporated and the residue-..taken up in hydroxypregn-4-en-3-one in 500 ml. of anhydrous'benzene, there were added. 75 ml. of 1% p-toluenesulfonie acid in benzene and then 35 ml. of dihydropyran'Thereaction mixture wasallowed. to stand atroom temperature for 16 hoursawashed With 2% aqueous sodium bicarbonate and water, dried and concentrated in vacuo atql 1 5rnm.-- Hg and 80. The residue consisting of 200: and 'ZOB-tetra hydropyranyloxy-pregn 4-en 3-one was dissolved 'in2 liters ether. The ether extract was worked up and gave 20,8 hydroxy-l0ot-desA-pregnan-5-o ne,. M.P. 104l5-1 05 (crystal lized fromether-hexanel. r f

' EXAMPEE 1e70,

L10 g.:of a mixture of 20a1and 2o'fl-tetrahydropyranyh oxye5 oxo 3,5eseco A-nor-pregnandeoic acid lithium. salt was mixed with 15 gaeach of: anhydrous sodium acetate and anhydrous potassiumracetateand pyrolyzed6ate0.01-.

0.1-rnm..-Hg.and'290 for 5; hours. The distillate was idis solved inplQO ml. of .ethariol 'and; aften' the addition of 15 m1. of water and. 2 50 mg. of p-toluenesulfonic acid 

